The long-term goal of this project is to understand what mechanisms are involved in prostate cancer, which may help to discriminate aggressive, fatal types from indolent, less aggressive ones and develop an improved framework for choosing new drug targets. Interrogation of disease mechanisms and risk stratification could be accomplished by leveraging knowledge about inherited risk factors such as germline genetics. The ability to use the majority of inherited genetic information in the clinical setting has been limited because many popular analytic approaches are agnostic to gene structure and the role of gene products in biological mechanisms. This important context is not commonly integrated into studies of genome-wide genetics and often only referenced post-analysis to interpret significant findings. In answer to this problem, the proposed study will utilize pathway analysis, recent innovative approach for the study of germline genetics. This method is adapted from gene expression studies and investigates the effects of genetic variants from an entire set of genes that are related to one another through biological mechanisms or cellular functions, termed pathways. Pathways are treated as the unit of analysis rather than individual genetic variants, thus aggregating association signals and improving statistical power to detect true phenotype associations. The aims of this proposal are to identify the germline genetic pathways involved in aggressive prostate cancer development and disease progression, and determine whether any genes or pathways are shared between the two phenotypes. This will be accomplished by first estimating the combined effects of rare and common variants for each gene (Aim 1a), followed by the organization of these genes into pathways (Aim 1b), which will be tested against each other to identify those involved in aggressive prostate cancer development (Aim 1c). The process will also be conducted for a time to disease progression phenotype (Aim 2a); then genes and pathways involved in the development of both disease outcomes will be identified (Aim 2b). Shared genes and pathways may be promising targets for understanding what differentiates between latent and aggressive prostate cancer. Information about unshared genes and pathways can also highlight mechanisms that are important at only certain phases of cancer development. The interdisciplinary training environment for this proposal will provide the applicant an opportunity to gain technical skills, to build research competency, and to develop content area expertise for her career as a future independent researcher.